Altered regulation of glucose homeostasis is one of the hallmarks of diabetes mellitus. Glucose homeostasis is the net result of glucose utilization, lipolysis, glycogenolysis, gluconeogenesis and glycogenesis. These processes, primarily regulated by peptide and amino acid hormones which presumably act through cyclic AMP, achieve maximal rates only if glucocorticoid hormones are present. This important action of the glucocorticoids to amplify biological processes is a widespread phenomenon, yet the molecular mechanism is poorly understood. This proposal outlines a series of studies aimed at elucidating the molecular nature of the glucocorticoid-cyclic AMP interaction in gluconeogenesis. The experimental model emphasized in this proposal is the regulation of tyrosine aminotransferase (TAT) synthesis which, like the examples cited above, achieves maximal rates only when both glucocortocoids and cyclic AMP are present. We have developed a cell-free translational system which will be used for analyzing the effects glucocorticoids and cAMP, singly and in combination, have on the mRNATAT activity in liver and in cultured hepatoma cells. We intend to develop a cDNA probe to extend these studies. This proposal should be of interest for two reasons. First, we intend to provide a detailed description of how various hormones regulate the activity of a gluconeogenic enzyme; this is of importance since gluconeogenesis is probably increased in the obese, adult onset diabetic. Second, in studying the combined effects of dexamethasone and cyclic AMP on TAT induction, we offer a detailed approach to the general problem of how glucocorticoids act as biological amplifiers.